Discovery of a Potent and Selective DDR1 Receptor Tyrosine Kinase Inhibitor

The DDR1 receptor tyrosine kinase
is activated by matrix collagens
and has been implicated in numerous cellular functions such as proliferation,
differentiation, adhesion, migration, and invasion. Here we report
the discovery of a potent and selective DDR1 inhibitor, DDR1-IN-1,
and present the 2.2 Å DDR1 co-crystal structure. DDR1-IN-1 binds
to DDR1 in the ‘DFG-out’ conformation and inhibits DDR1
autophosphorylation in cells at submicromolar concentrations with
good selectivity as assessed against a panel of 451 kinases measured
using the KinomeScan technology. We identified a mutation in the hinge
region of DDR1, G707A, that confers >20-fold resistance to the
ability
of DDR1-IN-1 to inhibit DDR1 autophosphorylation and can be used to
establish what pharmacology is DDR1-dependent. A combinatorial screen
of DDR1-IN-1 with a library of annotated kinase inhibitors revealed
that inhibitors of PI3K and mTOR such as GSK2126458 potentiate the
antiproliferative activity of DDR1-IN-1 in colorectal cancer cell
lines. DDR1-IN-1 provides a useful pharmacological probe for DDR1-dependent
signal transduction.